A novel small molecule peptide CS6253 in the treatment of hereditary APOE4-associated dementia including Alzheimer's disease
Jan Johansson
CEO, Artery Therapeutics, Inc.
Artery Therapeutics, Inc. (ATI) is a San Francisco-Bay area clinical stage company laser-focused on the ATP binding cassette target. ATI's lead molecule CS6253, currently in Phase 1 studies is a small molecule peptide being developed for the indication of APOE4-associated dementia including Alzheimer's disease (AD).
In the US 5-6 million people have AD and APOE4 increases the AD-risk 12-fold, with the current treatment alternatives being contra-indicted for APOE4 AD because of vascular side-effects. ATI is developing a highly differentiated, cholesterol focused treatment with the CS6253 peptide. The impaired apoE4 - ABCA1 mediated cholesterol efflux is corrected by CS6253 as exemplified by increased cholesterol efflux and increased lipidation of apoE particles (Boehm-Cagan et al., 2016b, Rawat et al., 2019). The ABCA1 agonist CS6253 binds to ABCA1, prevents ABCA1 degradation, and increases ABCA1 protein concentration at cell membranes resulting in increased cholesterol efflux and lipidation of apoE (Hafiane et al., 2015, Boehm-Cagan et al., 2016b, Rawat et al., 2019). Increased lipidation of apoE is associated with amyloid scavenging, prevention of amyloid aggregation and subsequently transporting amyloid out of the brain.
CS6253 by regulating ABCA1 levels and apoE lipidation in the brain influences several important down-stream pathways including amyloid production, degradation and transportation, as well as P-tau biology (Boehm-Cagan et al., 2016b, Rawat et al., 2019), which together with cholesterol homeostasis we postulate is responsible for inhibiting AD pathogenesis.
Developing a small molecule peptide like CS6253 for APOE4 AD provides several interesting development-challenges of which we hope to illustrate a few.
For example, the APOE4 genotypes makes it possible to identify and start AD-prevention early. Also, CS6253 has excellent PK, toxicology and bioavailability properties suggesting that CS6253 can be self-administered once or twice weekly for maximal convenience and compliance.
Jan Johansson, CEO, MD, PhD, was trained as a basic scientist, has practiced cardiovascular medicine for 18 years, and has a background in translational and development of cardiovascular technologies and, for the last decade, extensive experience in neurodegenerative disease. He has published more than 100 peer-review articles and more than 30 patents. Dr. Johansson has led basic research groups, supervised small molecule and peptides discovery programs and led clinical Phase 1-3 programs, and registered one therapeutic. Dr Johansson is the PI of ATI's NIH SBIR Fast-Track grants for the CS6253 IND and first-in-human trial. He has as founder and/or corporate officer taken 3 companies public in North America.